Cells and Synapses:
The brain, like all organs of the body, is made up of discrete cellular elements. It is the interactions between the cells of the brain that allows organisms to behave, learn, remember, consider abstract concepts and create ideas; to form language, mathematics to music.

There are two types of cells in the brain; neurons and glia. Neurons are the cells that are involved in the processing of information; they receive signals from sensory organs or other neurons; and they integrate information and transmit it. The cellular mechanisms used by nerve cells or neurons, are for the most part similar to those used by other cells of the body; however they differ from the other cells of the body in two important ways:

First, once neurons have differentiated, they never divide again. Thus, once they are damaged or destroyed, they are not replaced, unlike the cells of other organs (but see the end of this paragraph). In the human brain there are between 100 billion nerve cells (and many more glia) with approximately 100 trillion connections. The brain of a 1 year old human contains as many cells as it will ever have, and cells are constantly lost throughout life. We probably lose about 200,000 neurons per day, but because we have so many, most of us can get through life without detecting this loss; however if one lives long enough, mental deficits or Alzheimer's-like symptoms are seen in most people (caveat about stem cells in the hippocampus and lining of ventricles). (Caveat: stem cells remain in the brain; the layer around the ventricles remains one cell layer thick and can still divide; stem cells in the dentate gyrus keep on dividing and olfactory neurons renew themselves continually).

Neurons also differ from other cells in their need for oxygen. Deprived of oxygen, nerve cells will die within a few minutes. Neurons cannot build an oxygen debt as can muscle cells or other cells of the body; that is, they cannot survive anaerobically. This constraint, has, of course, enormous medical implications. When oxygen flow is cut off, brain cells die first.

Glial cells (literally neuroglia = 'nerve glue') are supporting cells whose functions are not entirely understood. They do not appear to participate directly in information processing, although their membrane potentials fluctuate when the brain is functioning (although it is true that all cells of the body maintain a membrane potential difference between the inside and outside of cells because of the ion imbalances). They are much more numerous than neurons and fill up the extracellular spaces between neurons, providing a structural framework, particularly during development. They also make up the insulating myelin sheath that surround nerve cells axons and they regulate the concentration in the extracellular space of things like ions and neuroactive substances released from the neurons.

There are two categories of glia cells in vertebrates:

Macroglia: the two classes are;

astrocytes which are star shaped cells with many processes and often with numerous filaments (structural framwork)

oligodendrocytes, which mainly help to make up the myelin sheath. (in the peripheral nervous system the myelin sheath is made up of macroglial cells called Schwann cells).

Microglia: these are small glial cells which serve, among other duties, as macrophages - cells that phagocytose (eat) dead cells or other debris.

Neurons are varied in form. Most have numerous and often long processes that allow the cells to contact one another in complex and intricate ways. Processes account for more than 90% of volume in many nerve cells; thus much of the brain is made up of processes. Also, only a small percentage of the synaptic contacts are on cell bodies, so the overwhelming majority of interactions in the brain occur between neuronal processes.

Each part of the brain has neurons with unique shapes, presumably related to the function of the cells and of that part of the brain.

How nerve cells can be grouped:

Classification of neurons on the basis of their structure, function and chemistry is an active area of research; by discovering the role of specific cells in each part of the brain, it is hoped that we will gain insights into brain mechanisms and function

Within each brain region you can classify the neurons into distinct types; each of which looks similar and tends to have similar functions (such as in brain nuclei).

Anatomists further subdivide cell types into subtypes (such as multipolar (one axon, many dendrites), bipolar (1 dendrite and 1 axon) and unipolar (one axon, no dendrites on cell body) to name one way of grouping by shape) of which there are many. Correlations between anatomical and physiological subtypes have been made in many cases. Many subtypes of cells have specific neuroactive substances they employ to communicate information.

Nerve cells can also be grouped into two broad classes, which Ramon y Cajal termed Golgi Type I and Golgi Type II. Santiago Ramon y Cajal (1852-1934) was a Spanish physiologist and histologist who won the Nobel prize in 1906 (with Golgi) for 1) describing neuronal processes; 2) discovering how to stain neurons and 3) describing structures in the CNS.

Golgi Neurons:

Golgi Type I neurons:

Long-axon neurons that carry information from one part of the brain to another (that is, from one nucleus or nuclear layer to another), or from the brain or spinal cord to effector organs such as muscles. See multipolar neuron picture.

They are larger than Golgi Type II neurons.

Primary, secondary and tertiary dendrites can be distinguished and the finest dendrites often have small lollipop-shaped spines on them. On the spines can be found much of the synaptic input to many Golgi Type I cells.

Each neuron has just one axon, which, as it comes off the cell body, is thinner than the primary dendrites. It remains roughly the same size throughout its length, and usually branches, if at all, only a few times near its termination.

Virtually all of the input to Golgi Type I neurons is onto the dendrites or cell bodies and output occurs at the axon terminals (one way information transfer). Dendrites transmit information to the cell body, and axons transmit messages away from the cell body.

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Golgi Type II neurons:

Neuron is characterized by having short, or sometimes no, axons.

Have smaller cell bodies than do Type I neurons

Do not send processes from one part of the nervous system to another. Rather, their processes are usually confined to a single nucleus or layer. Golgi Type II neurons are involved in local interactions between nerve cells and are often called association neurons

Dendrites and axons of Type II neurons are often both pre- and post-synaptic. That is, the dendrites are not exclusively receiving input, nor are the axons exclusively providing output, as in Golgi Type II neurons. Rather, both dendrites and axons can both receive and make synaptic contacts.

Cajal pointed out that the brains of more highly developed animals contain more Golgi Type II cells than Golgi Type I cells; and that the main difference between the mouse and primate cortex was in the relative number of Golgi Type II neurons. Local circuits of this type are thought to be important in mediating subtle neuronal interactions.

Myelin Sheath:

All axons are encased in glial cells. Two arrangements are possible:

unmyelinated neurons: small axons are simply surrounded by glial cells and a single glial cell may surround several small axons.

myelinated neurons: around larger axons, glial cells wrap themselves around the axon and form the myelin sheath. In the CNS, one oligodendrocyte forms myelin around many axons, perhaps as many as 50; but many oligodendrocytes are required to sheath an entire axon. Most axons in the vertebrate brain are myelinated.

The myelin sheath forms by the process of a glial cells surrounding the axon, at first much as do the glial cells of unmyelinated axons; with time, the glial cells wraps its membrane around the axon, with the number of wraps depending on the size of the axon; the larger axons have more wraps. The glial cell's cytoplasm is squeezed out, leaving behind layers of membrane from which much of the protein is lost. What remains is a compact layer of glial cell membrane with a high lipid content.

Along the length of an axon, the glial sheath is not continuous; but is interrupted by patches of myelin-free patches called the nodes of Ranvier (after their discoverer). The distance between the nodes varies, with larger axons having larger distances between nodes; the average is about 1-4 micrometer; one glial cell contributes myelin to just one internodal region.

Note that in some glial cell cytoplasm still exists in the myelin sheath close to the node and there are also specialized junctions lie between the glial sheath and the axon. It is suggested that both of these structural features play a supportive or nutritive role in the nodal area of the axon.

Synapses:

The functional contacts or synapses between neurons are of utmost importance for understanding brain mechanisms because it is here that neurons are excited, inhibited or modulated. Modifications of synapses are thought to underlie phenomena such as learning and memory. One any one cell hundreds to thousands of contacts are made. The champion in number of contacts is probably the Purkinje cell of the cerebellum, which may have as many as 100,000 synapses on its dendritic tree). Most synaptic contacts in the brain are chemical; that is a substance is released from the presynaptic side of the terminal, diffuses across a narrow (20 - 40 nm) cleft of extracellular space and interacts with specific receptor sites on the postsynaptic side of the contact. Electrical synapses are also known, but are less common.

Chemical synapses:

On the presynaptic side of the junction, synaptic vesicles store the neuroactive substances to be released by the terminal. Synaptic vesicles are typically clustered close to the presynaptic membrane, and it appears that they may be bound to the membrane. In the extracellular space between the pre- and post-synaptic membrane, filaments are often observed; the function of these filaments are not understood, but they may anchor the two sides of the junction together.

In many parts of the brain, two anatomical types of chemical synapses are distinguished; Type I and Type II (first described by George Gray).

The Type I synapse is an excitatory synapse (usually using glutamate or acetylcholine as a neurotransmitter) and is found mainly on dendrites. It is characterized by spherical synaptic vesicles of 40 nm in diameter, a widened synaptic cleft and prominent electron-dense material on the post-synaptic membrane.

Type II is an inhibitory junction (usually using GABA [gamma-aminobutyric acid] or glycine as a neurotransmitter), and is found mainly on cell bodies. The vesicles in type II are generally flatter and have dimensions of 25 nm by 50 nm. The cleft is not widened and the specialized structures that appear on the postsynaptic membrane in electron micrographs are in clusters, not evenly distributed.

Ions:

Atom = smallest particle of an element which retains the chemical properties of the element.

Atoms are composed of three primary types of particles, electrons, protons and neutrons. The nucleus or core of the atom is made up of protons with positive electrical charges and neutrons with no charge. The electrons, negatively charged particles, are found in the space around the nucleus. An atom has no electrical charge, since the positive protons balance the negative electrons. However, atoms can gain or lose negative electrons and become an ion, which can then have either a positive or negative charge.

So, for example a Lithium atom that has three protons (positive charges) and three electrons (negative charges), can lose one of its electrons to form a Lithium ion which has a positive charge (Li+). The plus indicates that there is one more proton in the atomic nucleus than electrons surrounding the nucleus. Atoms can also gain electrons; so for example, a fluorine atom with 9 protons and 9 electrons can gain an electron and thus gain a negative charge (Fl-).

Structure and Electrical Properties of Membranes:

All electrical potentials in biological systems are generated across cell membranes, and depend on the properties and constituents of cell membranes for their generation.

All membranes consist of a lipid bilayer in which proteins are imbedded. Phospholipids, the predominant lipids found in membranes, are made up a glycerol backbone to which are attached two long fatty-acid chains and a shorter phosphate-linked alcohol molecule. A key feature of phospholipids is that the glycerol and phosphate-linked alcohol are highly hydrophilic (have a strong affinity for water), whereas the fatty-acid chains are highly hydrophobic (weak affinity for water). In simple terms, one end of the molecule seeks water and the other avoids it. The consequence is that these lipids spontaneously form bilayers in aqueous solutions with the hydrophilic heads on the outside and the hydrophobic tails on the inside. Because the interior of the bilayer excludes water, the lipid part of the membrane is highly impermeable to ions and other water-soluble substances.

The movement of ions and small molecules across the membrane is regulated by the membrane proteins, which form aqueous pores or channels through the lipid bilayer or pump ions or molecules across the membrane. Most membrane proteins occupy the entire thickness of the membrane; in many membranes the proteins can move laterally; the viscosity of the membrane may be as fluid as that of a light motor oil; some proteins also appear to be anchored by attachments to other proteins and cytoskeleton components located just under the membrane.

There are five basic types of ion channels found in nerve cell membranes that we will be concerned with:

Leak channels account for the natural permeability of membranes to ions (although they may be permeable to just one ion) (responsible for helping maintain resting potential).

voltage-sensitive channels vary in permeability depending on membrane voltage; they are found mainly in axons (responsible for propagation of action potential)

Ligand-sensitive channels respond to specific chemical agents and open or close in the presence of that agent; they are found in dendritic and cell body membranes at postsynaptic sites (responsible for IPSPs and EPSPs).

electrogenic pumps: channels which are active, energy using pumps that pump ions across the cell membrane. One kind is the sodium-pottasium pump, that pumps Na out and K into the cell to maintain the resting potential.

Mechanosensitive channels respond to deformation of the channel or the membrane surrounding the channel; they are found in certain receptor cells (later in sensory systems).

Most channels show a high degree of ion specificity; they may even discriminate between closely similar ions such as Na+ and K+.

Resting potentials:

Neurons at rest typically maintain a voltage across the membrane of between 60 - 70 mV. The inside of the cell is negative relative to the outside, so the membrane potential is conventionally written as -60 to -70 mV. The membrane potential represents an unequal distribution of charge on the two sides of the cell membrane; that is, an excess of negative charge inside the membrane; and an excess of positive charge on the outside of the cell. The charge is carried by ions, and the unequal distribution of charge results from:

a difference in the concentrations of various ions inside and out

a difference in the permeability of the membrane to different ions.

Ions during Resting Potential:

At rest, this is the situation of a neuron. Inside cells, the major cation (positive ion) is potassium (K+), outside it is sodium (Na+). The major anions (negative ions) inside are small, organic molecules (A-) such as aspartate, acetate, pyruvate or isothionate, while outside chloride (Cl-) is the major anion.

There is relatively little Na+ inside the axon relative to the outside; whereas there is much more K+ inside than outside. There is considerably more Cl- outside than inside and the concentration of organic anions is high inside and virtually nonexistent outside the axon.

At rest, the inside of the axon contains lots of K+, little Na+ and Cl- and lots of anions. Outside the cell, there is lots of Na+, Cl-, but little K+ and no anions.

The permeability of the nerve cell membrane at rest is also different for the different ions. The membrane is most permeable to K+, but only sparingly permeable to Na+ (via leak channels). Permeability to Cl- is intermediate between that of K+ and Na+, while the membrane is essentially impermeable to the organic anions A-. It is important to remember that the membrane is not freely permeable to K+. If that were so, nerve cell membranes would have little electrical resistance, which is not the case. Of the major ions on the inside and outside, however, the membrane is considerably more permeable to K+ than to other ions.

With different concentrations on either side of the membrane, ions try to move down a concentration gradient, from an area of high concentration to one of lower concentration (diffusion pressure or osmotic pressure-gradual mixing of molecules of two or more substances owing to molecular movement). The ions Na+ and A- cannot move across the membrane to any appreciable extent because of the low permeability of the membrane to these ions. The ions K+ and Cl- can cross the membrane; and K+ does so because there is diffusion pressure on it to move down its concentration gradient; since there is less K+ outside than inside. Every time a K+ ion leaves the inside of the membrane, the negative charge on the inside gets greater, and the positive charge on the outside gets bigger. The resulting charge separation establishes a voltage across the membrane, that is, a resting potential.

K+ cannot equilibrate completely because as K+ leaves the cell and makes the inside more negative, an electrostatic force pulls the K+ back inside (that is, K+ moves into the cell in response to a charge gradient, positive charges are attracted to negative charges). In other words, the system reaches an equilibrium in which the diffusion pressure on K+ to leave the cell is balanced by the electrostatic attraction of the negative charge pulling the positive ions back in.

Na+:
Even though the Na+ permeability of the membrane at rest is low, some Na+ does cross the membrane and with time accumulates inside the cell. The addition of positive charges inside the cell also allows more K+ to leave. Eventually, the concentration differences between inside and out would be abolished, so removing Na+ from inside a cell is critical.

Cell membranes possess active ion pumps that require an energy source (usually ATP). The most common is a Na+-K+ exchange pump in which Na+ is pumped out of the cell while K+ is pumped in. Most of the pumps pump out more Na+ than they pump in K+ - usually 3 Na+ ions for 2 K+ ions. These are called electrogenic pumps because they add to the membrane potential.

Action Potentials and Their Propagation:

A popular experimental preparation to study action potentials is the giant axon of a squid - these giant axons can be up to 1 mm in diameter. If you put a giant axon of the squid in sea water, the concentrations of ion in the seawater approximates those of the blood of a squid; and you can easily insert an electrode into the axon to measure action potentials.

If you had such a preparation and were to pass a small amount of current (the movement of ions) into the axon, the voltage across the membrane would change in accordance with the polarity of the current (positive or negative. As long as the change in membrane voltage is less than 15 mV, the response by the axon would be passive.

However, if the current is great enough to change the membrane voltage by about 15 mV in a positive (depolarizing) direction (from - 70 to more than - 55 mV), what is seen is an explosive change in membrane potential. The voltage rapidly reverses across the cell membrane, and the inside of the cell becomes positive relative to the outside. Within about 1 ms, the voltage across the membrane rises to about +50 mV and then rapidly falls. Within another millisecond or so, the voltage plummets to about -90 mV and thereafter returns to resting levels of -70 mV. This explosive and rapid change of membrane voltage is the action potential; (negative, hyperpolarizing changes never produce this active response, it is always passive).

What causes this rapid depolarization of the axonal membrane? The membrane suddenly becomes much more permeable to Na+; and this occurs because of the membrane voltage. At rest, the membrane is about 30 times less permeable to Na+ than to K+. But, as the membrane becomes depolarized, it becomes more permeable to Na+, although why this occurs is not entirely understood.

What we do know is that when the membrane depolarizes, a change in conformation (a change in the arrangement of the molecules) is induced in the channels and they open.

Thus, with depolarization, membrane permeability or conductance to Na+ increases, and with an increase in Na+ conductance, Na+ enters the axon, causes more depolarization and increases Na+ conductance even more. The system acts as a positive feedback loop, resulting in an accelerating, regenerative response.

The response becomes regenerative when Na+ current coming in exceeds the rate at which K+ can leave the cell; if the membrane voltage is depolarized by less than 15 mV, K+ ions can leave the cell as rapidly as Na+ ions enter the cell. Positive charges do not build up in the cell and regeneration does not occur. However, if the membrane voltage is depolarized by 15 mV or more, Na+ ions enter the cell more rapidly than K+ can leave, resulting in the all-or-none action potential.

Following the initiation of an action potential, Na+ permeability remains high for only about 1 ms; thereafter the membrane becomes more permeable to K+. Both Na+ and K+ conductances are dependent on both voltage and time. That is, the conductance changes for Na+ and K + are caused by changes in membrane voltage, but the timing of the changes differ. Upon depolarization, Na+ conductance rapidly increases, but then shuts down to resting levels within 1 ms K+ conductance, in contrast, rises slowly upon membrane depolarization and falls only as membrane voltage decreases.

As I said before, we know that when the membrane depolarizes, a change in conformation (a change in the arrangement of the molecules) is induced in the channels and they open; this figure shows a schematic model of what it thought to be occurring.

The channel is a transmembrane protein with two gates; an activation gate and an inactivation gate. The activation gate is closed at rest while the inactivation gate is open. Upon depolarization of the membrane, the activation gate opens. This allows Na+ ions to flow across the membrane, into the cell. The activation gate may close and reopen, but then the inactivation gate closes and shuts off any further flow of Na+ ions. With time the inactivation gate reopens, but slowly. The refractory period is the time during which the inactivation gate is closed (about 1.5 ms). No amount of depolarization can open the channel during the refractory period.

A diagram of the K+ channel (which is separate from the Na+ channel) would differ from the Na+ channel in having no inactivation gate. Upon depolarization, the activation gate in the K+ channel opens, but only after a delay of about 1 ms.

During the generation of an action potential, Na+ ions flow into the axon. Positive current spreads down the inside of the axon and neutralizes the negative charge on the adjacent membrane, thereby depolarizing it. With depolarization of the membrane, Na+ permeability increases, leading to further depolarization and eventually to the generation of an action potential across that bit of membrane. As this action potential is generated, the next bit of membrane is depolarized, leading to further action potential generation. In this way the action potential is continuously generated down the axon.

Action potentials move down the axon in only one direction, but current flowing into the axon at the site of impulse generation moves in both directions; why doesn't the action potential move in both directions? This is because of the refractory state of the Na+ channels following impulse generation. For about 1.5 ms following an action potential, the membrane cannot be induced to generate another impulse regardless of membrane voltage; since it takes time for the inactivation gates to open following the generation of an action potential. In addition, K+ conductance is still high; therefore more Na+ must come in than usual to generate an action potential. Thus the threshold for an action potential is elevated.

The rate of action potential transmission depends partly on the axon's diameter (this lowers internal resistance); the other mechanism which can increase speed of transmission is myelination (which is the strategy of vertebrates). Myelin significantly decreases capacitance; by increasing the thickness of the phospholipid surrounding the axon. Myelin also provides another important advantage, in that action potentials along myelinated fibers jump from one node of Ranvier to another, rather than being generated all along the length of the axon. In between nodes, the spread of potential is passive. An important advantage of myelinated axons is that active membrane (membrane containing Na+ and K+ channels) is restricted to the nodes; which means there is less metabolic drain on the fibers since they have to make and maintain fewer ion channels and pump fewer ions in and out of the cell. Because myelination also speed conductance, myelinated fibers can be much finer than unmyelinated ones and perform as effectively and more efficiently. It has been estimated that without myelin, the human brain would have to be 10 times larger to do what it does, and we would have to eat 10 times more food to maintain it.

Synaptic Potentials:

All neurons, are, in sense, chemoreceptors; they respond to chemicals released at synaptic sites.

Synaptic transmission begins with depolarization of the membrane of the presynaptic terminal. Voltage-sensitive CA2+ channels, present in the presynaptic membrane, open upon depolarization and admit CA2+ into the terminal. The Ca2+ facilitates the binding of synaptic vesicles to the presynaptic membrane by a mechanism not well understood. The synaptic vesicles become confluent with the terminal membrane, open, and release their contents into the synaptic cleft. The electron-dense projections observed by high-resolution electron microscopy along the presynaptic membrane may help bind the synaptic vesicles to the membrane; and Ca2+ promotes the attachment of synaptic vesicles to the dense projections.

(Not everyone agrees that transmitter is released by synaptic vesicles. Some maintain that it is released from the cytoplasm of nerve terminals and that the vesicles simply store neuroactive substances. It appears that some synapses may operate this way; since at some synapses vesicles are not seen to bind to the presynaptic membrane and calcium is not needed for transmitter release. However, it appears that the great majority of transmitter release is mediated through vesicles.)

This figure shows a simplified drawing of a golgi type I neuron; excitatory synapses impinge on its dendrites, whereas inhibitory synapses are found on the cell body. Action potentials travel down the innervating axons and depolarize the terminals synapsing on the neuron. This results in the release of neurotransmitter from the terminal buttons. The transmitter diffuses across the synaptic cleft to the postsynaptic membrane, where it causes a small voltage change. The small depolarization, called an excitatory postsynaptic potential (EPSP) occurs at membrane sites postsynaptic to excitatory synapses; at sites postsynaptic to inhibitory synapses, a small hyperpolarization, an IPSP occurs (inhibitory postsynaptic potential).

At each postsynaptic site, such potentials are elicited. Individual EPSPs and IPSPs are too small to have much effect on the neuron. But when many synaptic events are summed, they change the postsynaptic membrane substantially; the output of the cell reflects the balance of excitatory and inhibitory input onto the neuron. Excitatory input drives the membrane potential from rest to above action potential threshold levels, whereas inhibitory input lowers the membrane potential, often below threshold levels.

Action potentials are usually generated at just one locus in a neuron, the axon hillock. This region has the lowest threshold for action potential generation; this is because the voltage-sensitive Na+ and K+ channels are highly concentrated in the axon hillock membrane, and few of these channels are in the cell body or the dendrites (no action potentials are generated across the cell membrane of the soma).

When EPSPs occur, current (mainly Na+ ions) flow into the cell at the synapses and from there current flows down a the dendrites into the cell body, resulting in an overall depolarization of the cell. When a the axon hillock region is depolarized, an action potential is generated and then propagated down the axon. Current flows into the cell at each postsynaptic site and out of the cell along the membrane through leak channels, a term used to describe the non-gated channels in the membrane that are involved in establishing the cell's resting potential. Because current flows in at the synapse and flows out elsewhere, synaptic potentials are largest at the site of origin and voltage decays away from that site. Even though the membrane is not depolarized adjacent to the postsynaptic sites, synaptic potentials influence a neuron by their effect on the axon hillock membrane, where the action potential is generated.

Why is the neuron organized this way? Why aren't action potentials generated adjacent to the synaptic sites? Because if they were generated all along dendrites, impulses would travel along the dendrites in different directions, collisions would occur, refractory periods would prevent some membranes from responding, and so forth. In other words, the output of the cell would not necessarily reflect its synaptic input. Thus the axon hillock serves as a summing point of the neuron; it responds to the net balance of excitatory and inhibitory input to the neuron and orchestrates a coherent output for the cell.

Dendrites are usually quite thick compared to axons, and they have a low internal resistance, so that the spread of current is facilitated from the dendrite to the cell body. Nevertheless, because the spread of potential is passive and thus degrades with distance, synaptic potentials produced on the distal tips of dendrites are considerably attenuated before they reach the axon hillock. This suggests that synaptic input onto distal dendrites may have little or no effect on a cell's firing rate; it turns out that some dendrites have patches of membrane containing voltage-sensitive Na+ and K+ channels and that they can generate an action potential. It appears that these action potentials are not propagated, but are generated in strategic locations in large dendritic trees to ensure, presumably, that a synaptic input has a significant effect on the cell's output.

What is neurotransmitter doing to the postsynaptic membrane to produce synaptic potentials? Because current flows across the membrane at postsynaptic sites, an obvious suggestion is that NTs change membrane permeability and allow one or more ions to enter or exit the postsynaptic cell; since the permeability of these channels alters in response to NT, not voltage, they are called transmitter- or ligand-sensitive channels.

EPSPs:
The NT eliciting an EPSP opens a channel that allows NA+ to cross the membrane.

IPSPs:
Observations suggest that NT released at inhibitory synapses opens channels in the membrane specific for Cl-. Since Cl- concentrations are higher outside the cell than inside, Cl- moves inside and hyperpolarizes the cell. It appears that in other cases, K+ channels appear to be opened, since K+ concentrations are higher inside than out, K+ exits the cell and also hyperpolarizes it. At some inhibitory synapses, the inhibitory NT can open both Cl- and K+ channels.

The channels in postsynaptic membranes that open in response to NT are clearly different from the voltage-gated channels present in axon hillocks and axonal membranes. But transmitter- or ligand-gated channels, like voltage-sensitive channels, open in an all-or-none fashion when the appropriate NT is present in the synaptic cleft. The channels continue to open and close as long as NT is present.

Neurotransmitters;
- these substances act directly on the postsynaptic membrane and allow ions to flow across a channel in it;

- they mediate the fast EPSPs and IPSPs that lead to excitation or inhibition. EPSPs and IPSPs typically begin within a fraction of a millisecond after NT is released and they seldom last longer than 10 - 100 ms.

- The type of receptor which mediates this fast, ion channel type of action is called ionotropic.

Neuromodulators:
- Other substances modify neural activity, rather than initiate it. These substances are called neuromodulators;

- their effects usually have a slow onset (seconds) and their effects can last for minutes, hours or longer.

- There is good reason to believe that long-term changes in the brain, which underlie such phenomena as learning and memory result from neuromodulatory activity.

- Neuromodulators bind to receptors which interact with second messenger systems and are called metabotropic.

- interact with specific receptor proteins on the postsynaptic membrane linked to intracellular enzymes. Activating these receptors does not directly change membrane voltage or membrane resistance; rather, the action of the NM is mediated through biochemical changes in the postsynaptic neuron. The physiological changes mediate by NM typically have long latencies, on the order of seconds and changes can last for minutes, hours or even longer.

- Cyclic AMP and cAMP-dependent kinases can have effects at several levels in the cell - from the nucleus to the cytoplasm, to the membrane. In the nucleus, gene transcription can be altered; in the cytoplasm, protein synthesis or enzyme activity can be modified; and at the membrane, ion conductances can be modulated (via; 1) the frequency of opening of a channel; 2) the duration of opening of a channel; 3) the ionic specificity of the channel; or 4) the number of active channels in a piece of membrane.

- Neuromodulators can also have presynaptic effects as well as postsynaptic effects. Synaptic terminals can have their own receptors, called autoreceptors, that respond to the substance released by that terminal. In this example, the autoreceptors are linked to a cyclic AMP cascade. Activation of a kinase by cyclic AMP can modify enzymes involved in the synthesis of neuroactive substances in the terminal. Thus, the release of a neuromodulator from a synaptic terminal can regulate by a feedback mechanism the synthesis of that or other neuroactive substances.

Some neuroactive substances act exclusively as NT, some as NM, but many do both. ACh is an example; it acts on ACh channels at the NMJ and many other synapses; but it also acts on ACh receptors linked to an enzyme in the membrane. These two actions of ACh can be distinguished pharmacologically; with certain drugs blocking one but not the other. Two or more neuroactive substances can exist in single terminal, and frequently one of the neuroactive substances is a transmitter and the other is a modulator. Thus both actions can be initiated by the same synapse.

It is generally believed that neurons release the same substances from all of their terminals. This is known as Dale's law, after an English pharmacologist who first proposed this idea. It is further supposed that two or more neuroactive substances reside in one terminal of a neuron, that they are present in all terminals. There is evidence, however, that some terminals of a neuron release proportionally more of one neuroactive substance than do other terminals of the cell; indicating that the output of all terminals of a particular neuron may not be identical.

Classes of Neuroactive Substances:

Neurotransmitters:

Acetylcholine: ACh is generally classed as a separate kind of neuroactive substance, though technically it is a monoamine. It is the only naturally occurring substance in its class, but some synthetic substances are known which mimic it. It is found in both the CNS and the PNS, it was the first neuroactive substance to be found and characterized and is the most studied.

It is usually an excitatory NT, but is also known to have some inhibitory effects, such as the slowing of the heartbeat.

The important point here is that whether a neuroactive substance is excitatory or inhibitory, or acts as a NT or NM, depends on the receptor protein in the postsynaptic membrane to which it binds. If the receptor is part of a channel, the substance acts as a NT. The channels ion selectivity then determines whether the effect is excitatory or inhibitory (excitatory = Na+; inhibitory = Cl-). The substance can act as a neuromodulator if it interacts with a receptor linked to a G-protein. The action that is mediated by this interaction with the G-protein will depend on the enzymes or channels affected by the G-protein; the second messengers that are produced (if any) and the kinases (if any) activated by the second messenger.

Amino Acids:
Amino Acids act primarily as NT and are believed to be the principal excitatory and inhibitory NT in the brain. There are two well-established excitatory AAs; L-glutamate and L-aspartate; and two well-known inhibitory AAs, gamma-aminobutyric acid (GABA) and glycine.

Neuromodulators:

Monoamines:

Catecholamines: dopamine, norepinephrine, epinephrine

Indolamine: serotonin

These are the two classes of monoamines and the 4 kinds of monoamines that are released in the brains of vertebrates. These agents appear to have something to do with the brain's affective and arousal states. Substances that affect the levels or actions of the catecholamine and indoleamines often alter mood and other mental states.

What happens to NT or NM after it releases from the receptor site?

Removal of transmitter:
The next step is to rid the synaptic cleft of transmitter. At, for example, acetylcholine synapses, an enzyme, acetylchoinesterase, rapidly breaks down ACh to its component parts, acetate and choline; neither of which can activate the receptor unless bound.

Other neuroactive substances are cleared from the synaptic cleft by active reuptake of the substance into the presynaptic terminal. This is accomplished by transmembrane proteins called transporters. There are specific transporters for different neuroactive substances, and all transporters require Na+ to function. Glial cells may also take up neuroactive substances by similar Na+ mediated mechanisms and thus help terminate synaptic activity.

Resynthesis and repackaging of transmitter:
The last step is to restore the availability of transmitter for the next time it is needed for synaptic transmission. For example, for ACh, choline is actively transported back into the terminal and joined with activated acetate molecules within the cell to re-form ACh. At other synapses where transmitter is brought back up into the presynaptic terminal, the terminal membrane infolds and forms a new vesicle around the NT.

Central dogma of Neuroscience This simple scheme is the central dogma of neuroscience. Sensory stimuli from the environment impinge on receptors, which respond by producing receptor potentials, which in turn lead to the generation of action potentials which carry information substantial distances in the brain. As information passes from one neuron to another at synaptic junctions, synaptic potentials (graded potentials) are generated in the postsynaptic neurons which in turn can lead to action potentials. Receptor potentials can also lead directly to a synaptic potential in adjacent neurons. Effectors, such as muscles are activated by synaptic potentials, resulting eventually in behavior.

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